Project I: Summary/Abstract About two-thirds of patients with Parkinson?s disease (PD) experience falls. Falls in PD patients are a primary cause of hospitalization and nursing home admission. These debilitating features of PD are resistant to dopamine replacement therapy, emphasizing the critical need for basic research and therapeutic development focused on non-dopaminergic systems that degenerate in PD. During the initial funding period, we established a rodent model of PD falls and developed a novel behavioral paradigm that reflect many elements of PD falls. The novel Michigan Complex Motor Control Task (MCMCT) assesses falls resulting from impaired cognitive-motor interactions in rats. We also demonstrated that rats with dual losses of cortical cholinergic and striatal dopamine (DL rats), reflecting PET-based findings in PD fallers, exhibit high rates of falls on the MCMCT. Similar to PD fallers, impairments in attention of DL rats predict fall rates. Importantly, treatment with an ?4?2* nicotinic acetylcholine receptor (nAChR) agonist, or with combination treatments of ACh-esterase inhibitors (donepezil or rivastigmine) and a 5-HT6 receptor antagonist (idalopirdine) reduce fall rates, supporting the translational value of our system. We now propose rigorous systems-neuroscience analyses of the role of basal forebrain cholinergic signaling in falls (Aim 1), of cholinergically-driven cortico-striatal information transfer (Aim 2), and of the role of striatal cholinergic interneurons (Aim 3). The goals of the research of Aim 1 and Aim 3 will directly support the research of Projects III and II, respectively. The proposed research is supported by extensive preliminary evidence demonstrating 1) the impact of optogenetic manipulations of basal forebrain cholinergic signaling on complex movement control; 2) that cues guiding complex movements are ?imported? into the striatum via cortico-striatal glutamatergic activity; 3) that DREADD-based inhibition or stimulation of striatal cholinergic interneuronal activity cause and prevent falls, respectively; 4) and that these interneurons broadly code cues utilized to execute movements. Collectively, the proposed research will develop a cognitive and systems neuroscience approach to understanding falls in PD, establish a valuable preclinical model for therapy development, and substantiate falls as a useful behavioral endpoint for studying the cortico-striatal, cognitive- motor interface.